Field of the Invention
This invention relates to compounds for modulating multiple protein kinase enzymatic activities for affecting cellular activities such as proliferation, differentiation and programmed cell death. Specifically, the invention relates to quinazolines that inhibit, regulate and/or modulate a set of kinase enzymes and receptor signal transduction pathways related to the changes in cellular activities as mentioned above, compositions which contain these compounds, and methods of using them to treat kinase-dependent diseases and conditions. Even more specifically, the invention relates to the use of a kinase inhibitor compound that downregulates a unique group of kinases active in the progression of polycystic kidney disease (PKD) and to methods of treating PKD.
Summary of Related Art
The development of targeted therapy focused initially on the search for drugs that could specifically target a selected kinase enzyme essential for cell proliferation in cancer. The purpose of searching for selectivity was to try and limit toxicity. This approach was generally unsuccessful because it was difficult to achieve single kinase target inhibition due to the “overlap” and homology of the active kinase domains of the known 540 kinases. Secondly, it has become increasingly clear that focused targeting results in the selection for cells capable of circumventing any single point of inhibition in a pathway. Current thinking leans towards targeting multiple sites in single or multiple pathways. This observation, learned from experience in oncology can be applied to other diseases (as outlined below).
Protein kinases are enzymes that catalyze the phosphorylation of proteins, in particular, hydroxy groups on tyrosine, serine and threonine residues of proteins. The consequences of this seemingly simple activity are staggering, influencing cell differentiation and proliferation. Virtually all aspects of cell life in one-way or another depend on protein kinase activity. Furthermore, abnormal protein kinase activity has been related to a host of disorders, ranging from relatively non-life threatening diseases such as psoriasis to extremely virulent diseases such as glioblastoma (brain cancer).
Protein kinases can be categorized as receptor type or non-receptor type. Receptor-type tyrosine kinases have an extracellular, a transmembrane, and an intracellular domain, while non-receptor type tyrosine kinases are wholly intracellular.
Receptor-type tyrosine kinases are comprised of a large number of transmembrane receptors with diverse biological activity. In fact, about twenty different subfamilies of receptor-type tyrosine kinases have been identified. One tyrosine kinase subfamily, designated the HER subfamily, is comprised of EGFR (HER1), HER2, HER3, and HER4. Ligands of this subfamily of receptors identified so far include epithelial growth factor, TGF-alpha, amphiregulin, HB-EGF, betacellulin and heregulin. Another subfamily of these receptor-type tyrosine kinases is the insulin subfamily, which includes INS-R, IGF-IR, and IR-R. The PDGF subfamily includes the PDGF-alpha and beta-receptors, CSFIR, c-kit and FLK-II. Additionally there is the FLK family, which is comprised of the kinase insert domain receptor (KDR), fetal liver kinase-1 (FLK-1), fetal liver kinase-4 (FLK-4) and the fms-like tyrosine kinase-1 (fit-1). The PDGF and FLK families are usually considered together due to the similarities of the two groups. For a detailed discussion of the receptor-type tyrosine kinases, see Plowman et al., 1994 DN&P 7(6):334-339, which is hereby incorporated by reference for all purposes.
The non-receptor type of tyrosine kinases is also comprised of numerous subfamilies, including Src, Frk, Btk, Csk, Abl, Zap70, Fes/Fps, Fak, Jak, Ack, and LIMK. Each of these subfamilies is further sub-divided into varying receptors. For example, the Src subfamily is one of the largest and includes Src, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr, and Yrk. The Src subfamily of enzymes has been linked to oncogenesis. For a more detailed discussion of the non-receptor type of tyrosine kinases, see Bolen, Oncogene, 8:2025-2031 (1993), which is hereby incorporated by reference for all purposes.
Deregulation of protein kinase enzymatic activity can lead to altered cellular properties, such as uncontrolled cell growth associated with cancer. In addition to oncological indications, altered kinase signaling is implicated in numerous other pathological diseases. These include, but are not limited to: immunological disorders, cardiovascular diseases, inflammatory diseases, and degenerative diseases. Therefore, both receptor and non-receptor protein kinases are attractive targets for small molecule drug discovery.
One particularly attractive goal for therapeutic use of kinase modulation relates to oncological indications. For example, modulation of protein kinase activity for the treatment of cancer has been demonstrated successfully with the FDA approval of Gleevec® (imatinib mesylate, produced by Novartis Pharmaceutical Corporation of East Hanover, N.J.) for the treatment of Chronic Myeloid Leukemia (CML) and gastrointestinal stroma cancers (GIST). Gleevec is a c-Kit and Abl kinase inhibitor.
Modulation (particularly inhibition) of cell proliferation and angiogenesis, two key cellular processes needed for tumor growth and survival (Matter A. 2001 Drug Disc Technol 6:1005-1024), is an attractive goal for development of small-molecule drugs. Anti-angiogenic therapy represents a potentially important approach for the treatment of solid tumors and other diseases associated with dysregulated vascularization, including ischemic coronary artery disease, diabetic retinopathy, psoriasis and rheumatoid arthritis. Also, cell antiproliferative agents are desirable to slow or stop the growth of tumors.
Inhibition of EGF, VEGF and ephrin signal transduction will prevent cell proliferation and angiogenesis, two key cellular processes needed for tumor growth and survival (Matter A. 2001 Drug Disc Technol 6:1005-1024). VEGF receptors are previously described targets for small molecule inhibition.
The Eph receptors comprise the largest family of receptor tyrosine kinases and are divided into two groups, EphA and EphB, based on their sequence homology. The ligands for the Eph receptors are ephrins, which are membrane anchored. Ephrin A ligands bind preferentially to EphA receptors whilst ephrin B ligands bind to EphB receptors. Binding of ephrin to Eph receptors causes receptor autophosphorylation and typically requires a cell-cell interaction because both receptor and ligand are membrane bound.
Overexpression of Eph receptors has been linked to increased cellular proliferation in a variety of tumors (Zhou R 1998 Pharmacol Ther. 77:151-181; Kiyokawa E, Takai S, Tanaka M et al 1994 Cancer Res 54:3645-3650; Takai N Miyazaki T, Fujisawa K, Nasu K and Miyakawa. 2001 Oncology Reports 8:567-573). The family of Eph receptor tyrosine kinases and their ephrin ligands play important roles in a variety of processes during embryonic development and also in pathological angiogenesis and potentially metastasis. Therefore modulation of Eph receptor kinase activity should provide means to treat or prevent disease states associated with abnormal cell proliferation such as those described above.
The epidermal growth factor receptor (EGFR, HER1, erbB1) is part of a family of plasma membrane receptor tyrosine kinases that control cellular growth, proliferation, and apoptosis. The ligand for EGFR is the epidermal growth factor and dysregulation of the EGFR signal transduction pathway has been implicated in tumorigenesis and cancer progression, thus making it a clinically relevant target for novel anticancer treatments (Drevs J et at 2003 Curr Drug Targets 4, 113-121; Ciardiello F and Tortora G. 2001 Clin. Cancer Res. 7:2958-2970; Thomas M. 2002 Semin Onc. Nurs. 18:20-27).
EGFR is overexpressed in different human cancers, especially non-small cell lung cancer and glioblastomas. In these cancers, EGFR overexpression is commonly associated with advanced disease and poor prognosis (Baselga J et at 1999 Semin. Oncol. 26:78-83).
“Polycystic kidney disease” (PKD) refers to a group of monogenic disorders that result in the development of bilateral renal cysts ultimately leading to kidney failure. PKD is the most common of all life-threatening genetic diseases, and affects 12-15 million people worldwide. There are two major forms of PKD: autosomal recessive (ARPKD) and autosomal dominant (ADPKD). ARPKD is a less-frequently inherited form of the disease that often causes significant mortality in the first months of life. ARPKD is caused by a mutation in the PKHD1 gene, while ADPKD is caused by a mutation in either the PKD1 or PKD2 gene (and thus these forms are referred to as type 1 or type 2 ADPKD). These single mutations result in dramatic changes in the ability of renal tubular cells to maintain their planar polarity (position within the organ), and to control their proliferation. ADPKD is the most common inherited genetic disease. Because each individual has one normal allele inherited from their non-carrier parent, the dominant mutant gene does not manifest its effects until the normal allele is lost or inactivated. Thus, some patients develop symptoms in childhood while most become symptomatic by age 40 depending on when the normal allele is lost. The biochemical mechanism responsible for the clinical findings associated with PKD is thought to relate to abnormalities in calcium ion channels.
As noted above, PKD is characterized by the bilateral formation and growth of multiple cysts that lead to the alteration of the kidney architecture, deformed nephrons and renal failure. In ADPKD, cysts form when the proliferation of renal tubular cells leads to obstruction of normal tubular flow. The renal tubular cells that form the inner lining of the cysts retain their normal secretary functions and fill the cysts with fluid that contains many receptor ligands (signaling proteins) such as TGF-alpha and EGF (Wilson S J et at 2006 Biochim Biophys Acta July; 1762(7):647-55). As the cysts enlarge, the kidneys enlarge to as much as 20-30 pounds in late stage disease.
Human clinical symptom in ADPKD patients include abdominal and flank pain (as the cysts enlarge), hypertension, liver cysts, hematuria, infection and ultimately renal failure. No specific treatment for the prevention of the progression of PKD is available (Grantham J J 2008 NEJM 359:1477-1485).
Similarly, PKD affects approximately 38% of Persian cats worldwide, making it the most prominent inherited feline disease (Young A E et at 2005 Mammalian Genome 16:59-65). It mimics human disease and is secondary to a mutation in the PKD1 gene.